chr7-90271959-G-A

Variant names:

• chr7-90271959-G-A
• rs1554359685
• NM_001039706.3:c.860+1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001039706.3(CFAP69):​c.860+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,550 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CFAP69 NM_001039706.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.80
• Publications: 0 publications found

Genes affected

CFAP69 (HGNC:26107): (cilia and flagella associated protein 69) Acts upstream of or within sperm axoneme assembly. Located in cytoplasm and sperm midpiece. Implicated in spermatogenic failure 24. [provided by Alliance of Genome Resources, Apr 2022]

CFAP69 Gene-Disease associations (from GenCC):

• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 24

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06298655 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.1, offset of 6, new splice context is: agcGTatgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-90271959-G-A is Pathogenic according to our data. Variant chr7-90271959-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 523226.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039706.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP69	NM_001039706.3	MANE Select	c.860+1G>A		splice_donor intron	N/A	NP_001034795.2
	CFAP69	NM_001160138.2		c.806+1G>A		splice_donor intron	N/A	NP_001153610.1
	CFAP69	NM_001363438.1		c.860+1G>A		splice_donor intron	N/A	NP_001350367.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP69	ENST00000389297.8	TSL:1 MANE Select	c.860+1G>A		splice_donor intron	N/A	ENSP00000373948.4
	CFAP69	ENST00000418199.1	TSL:3	c.264G>A	p.Leu88Leu	synonymous	Exon 2 of 2	ENSP00000393339.1
	CFAP69	ENST00000497910.5	TSL:2	c.806+1G>A		splice_donor intron	N/A	ENSP00000419549.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456550 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724198

African (AFR) AF: 0.00 AC: 0 AN: 33266

American (AMR) AF: 0.00 AC: 0 AN: 44130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 85068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109428

Other (OTH) AF: 0.00 AC: 0 AN: 60188

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Spermatogenic failure 24 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.8
ClinPred		0.98	D
GERP RS		5.2
PromoterAI		-0.044	Neutral
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.62		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554359685; hg19: chr7-89901273;